Abstract
Danon disease is a severe X-linked disorder caused by deficiency of the lysosome-associated membrane protein-2 (LAMP-2). Clinical manifestations are phenotypically diverse and consist of hypertrophic and dilated cardiomyopathies, skeletal myopathy, retinopathy, and intellectual dysfunction. Here, we investigated the metabolic landscape of Danon disease by applying a multi-omics approach and combined structural and functional readouts provided by Raman and atomic force microscopy. Using these tools, Danon patient-derived cardiac tissue, primary fibroblasts, and human induced pluripotent stem cells differentiated into cardiomyocytes (hiPSC-CMs) were analyzed. Metabolic profiling indicated LAMP-2 deficiency promoted a switch toward glycolysis accompanied by rerouting of tryptophan metabolism. Cardiomyocytes’ energetic balance and NAD+/NADH ratio appeared to be maintained despite mitochondrial aging. In turn, metabolic adaption was accompanied by a senescence-associated signature. Similarly, Danon fibroblasts appeared more stress prone and less biomechanically compliant. Overall, shaping of both morphology and metabolism contributed to the loss of cardiac biomechanical competence that characterizes the clinical progression of Danon disease.
Highlights
Danon disease is a rare, severe X-linked disorder caused by deficiency of lysosome-associated membrane protein-2 (LAMP-2) and characterized by skeletal and cardiac myopathy, retinopathy, and intellectual disability [1]
ribonucleic acid (RNA) sequencing was performed for patient cardiac tissues and patient human induced pluripotent stem cell (hiPSC)-CMs cells and revealed more than 2000 genes differentially expressed (FDR 0.05) in the hiPSC-CM model and more than 200 in the tissue sample (FDR 0.1), comparing each to relevant healthy controls
Among the top 10 most abundantly expressed genes in the cardiac tissue was delta (14)-sterol reductase (TM7SF2) and pro-inflammatory chemokine (C-C motif) ligand 5 (CCL5). These regulatory events found a parallel in the hiPSC-CMs with upregulation of TM7SF2 (Figure 1B) and CCL21 (Figure 1C)
Summary
Danon disease is a rare, severe X-linked disorder caused by deficiency of lysosome-associated membrane protein-2 (LAMP-2) and characterized by skeletal and cardiac myopathy, retinopathy, and intellectual disability [1]. LAMP-2 is a major glycoprotein component of the lysosomal membrane and is involved in autophagy [2]. Danon disease is generally more severe in hemizygous males, who show initial symptoms of cardiac involvement at puberty (12 years old on average). These individuals almost invariably develop severe hypertrophic cardiomyopathy and arrhythmia, leading to death or need of heart transplantation (18 years old on average) [4,5]. Heterozygous females typically show signs of disease later in life, presenting with dilated or hypertrophic cardiomyopathy often with cardiac conduction disease and arrhythmia [6]
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